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© 2003 American Society for Clinical Oncology Long-Term Follow-Up of a Prospective Study of Combined Modality Therapy for Stage I–II Indolent Non-Hodgkin’s LymphomaFrom the Department of Haematology, The Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia; Departments of Lymphoma/Myeloma, Radiation Oncology, Hematopathology, and Biostatistics, The University of Texas, M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Peter McLaughlin, MD, Department of Lymphoma/Myeloma, Box 429, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: pmclaugh{at}mail.mdanderson.org.
Purpose: Standard therapy for patients with stage I–II indolent lymphoma has been involved-field radiation therapy (IF-XRT), which achieves 10-year disease-free survival in 40% to 50% of patients, with many of these patients cured. We investigated the potential for combined-modality therapy to increase the disease-free survival for such patients. Patients and Methods: A total of 102 eligible patients with stage I–II low grade lymphoma (International Working Formulation criteria) were enrolled from 1984 to 1992. Treatment comprised 10 cycles of risk-adapted chemotherapy (cyclophosphamide, vincristine, prednisone, bleomycin [COP-Bleo], and with doxorubicin added for some [CHOP-Bleo]) and 30 to 40 Gy IF-XRT.
Results: The patients’ median age was 56 years (range, 28 to 77), with follicular histology in 83%, bulky disease ( Conclusion: With prolonged follow-up, combined-modality therapy with risk-adapted COP-/CHOP-Bleo and IF radiation has attained higher rates of disease control and survival than previously reported with IF-XRT alone. This apparent improvement is being further explored in an ongoing randomized trial.
ALTHOUGH THE majority of patients with indolent lymphomas have disseminated disease at presentation, 19% to 33% will have apparently localized disease after completion of clinical staging procedures.1–3 From early surgical staging studies predating the widespread availability of computed tomography (CT) scanning, up to 60% of patients presenting with disease clinically confined to the upper torso had occult abdominal disease at staging laparotomy.4,5 For decades, the standard therapy for stage I–II patients has been involved-field radiation therapy (IF-XRT). Many large series, mainly retrospective, have reported similar outcomes, with 28% to 53% of patients remaining free from recurrent disease after 10 or more years, and having a low risk of disease recurrence beyond this time.6–10 As durable in-field control rates are above 90% with radiation doses of 28 to 30 Gy or more,6,8,11,12 the dominant sites of failure are systemic, likely attributable to occult disease being left untreated.6,13,14 Both staging laparotomy and extended radiation fields have been used with the intent of either detecting or eradicating sites of occult disease.7,9,15–17 These studies have shown an improved outcome for patients with laparotomy-staged compared with clinically staged disease.9,17,18 However, the superiority of extended-field or total lymphoid irradiation over IF-XRT remains unsubstantiated, despite the potential for greater toxicity.7–9,16,17 An alternative approach to improve on the efficacy of IF-XRT is the addition of chemotherapy. In retrospective analyses, our group19 and others20,21 have suggested possible benefit from this approach. The few reported randomized studies of combination chemotherapy have not confirmed any benefit; however, all lacked meaningful statistical power, with no study enrolling more than 26 patients with low grade histologies.22–25 One single-agent study of substantial size was performed by the British National Lymphoma Investigation from 1974 to 1981, and examined the effect of low-intensity oral chlorambucil for 6 months after IF-XRT in 148 patients, with a nonsignificant trend toward fewer relapses in the combination arm.26 We now report an updated analysis of a prospective study of combined-modality therapy in clinically staged patients with a median follow-up of 10 years. In our previous analyses, we reported a 5-year relapse-free survival of 82% and overall survival of 90%, with a median follow-up of up to 5 years.27–29
The study was open from February 1984 until December 1992, with 114 patients enrolled. Patient eligibility and staging procedures have been published in detail.27 In brief, patients with clinical Ann Arbor stage I–II low grade non-Hodgkin’s lymphoma by International Working Formulation criteria30 were eligible, without restrictions on the basis of age, organ function, or prior malignancy. Seven patients (6%) were subsequently found to be ineligible, due to diffuse large cell histology on review in two cases, stage III or IV disease in four, and withdrawal of consent before receiving any therapy in one, leaving 107 eligible patients. Given the changes in the histologic classification of diffuse low grade lymphomas, the diagnostic material was reviewed in these cases and reclassified according to the World Health Organization criteria.31 This review identified five patients with mantle cell lymphoma (MCL) who, although eligible according to the original protocol criteria, are excluded from this analysis. One patient who had refused further treatment after one cycle of chemotherapy in the absence of toxicity, and who was therefore excluded from prior publications,27,29 was considered eligible and included in the current analysis. In all patients, staging included bone marrow aspiration and biopsy (usually bilateral) and bipedal lymphangiography and CT scanning of the abdomen and pelvis, or both. Only one patient underwent a laparotomy, and this was as a diagnostic procedure. Serum beta2-microglobulin (ß2M) was measured from October 1985.
Therapy Because of both the small numbers of DSL/mucosa-associated lymphoid tissue (MALT) patients and their potential for clinical heterogeneity, these two categories were combined and the focus of much of the statistical analysis in this report is placed on the subset of 85 patients with follicular lymphoma.
Data Analysis Overall survival (OS) and time to treatment-failure (TTF) were calculated from the date of commencement of therapy using the method of Kaplan and Meier, and comparisons were made using the log-rank test. All causes of death were included in the OS analysis. However, patients who died from unrelated causes with no evidence of disease recurrence (n = 13 in this report) were censored at the time of death in the TTF analysis. Survival from relapse was measured from the date that relapse was first established to the date of death from any cause or last follow-up. Categorical data were compared using the Fisher’s exact test, and ordinal data using the Wilcoxon two-sample test or Kruskal-Wallis test, as appropriate. All reported P values are two-sided.
Patient Characteristics Patient characteristics are listed in Table 1  . The vast majority of patients, 85 of the 102, had follicular lymphoma. There were no statistically significant differences in the characteristics of patients with follicular small cleaved cell (FSC) and follicular mixed small and large cell (FM), although there was a trend for those with FM to have a higher incidence of elevated serum LDH levels (29% v 13%) and bulky disease ( 5 cm; 43% v 22%; each P = .09 to .10 [data not shown]). Sites of involvement of the 14 patients with MALT lymphoma were stomach in eight, nasopharynx in two, and salivary gland, breast, orbit, and soft palate in one each. Twenty-four patients (24%) had no residual disease detected after diagnostic biopsies.
Delivery of Therapy, Response, and Acute Toxicity As previously described,27,29 the delivered therapy deviated significantly from protocol specifications in 10 patients (9%). Five patients did not receive radiation therapy, and five, including one who also refused radiation, received significantly less chemotherapy than planned (zero to three cycles). All of these patients are included in this intent-to-treat analysis. Of the 78 patients with disease evident at the start of therapy, 77 (99%) attained a CR or CRu. Treatment was well tolerated. Although no hematopoietic growth factors were used, neutropenia less than 0.5 x 109/L was only seen in 21% of assessable cycles, and hospital admission was required in 8.8% of cycles.27 There were no deaths during therapy.
Treatment Failure The 24 patients with no residual disease at the initiation of therapy were as likely to relapse as other patients (P = .7), with 71% (± 9%) remaining free from treatment failure at 10 years.
None of the 17 patients with DSL or MALT histology have relapsed, with a median follow-up of surviving patients of 8 years (range, 2.5 to 14 years). There was a significant difference in TTF between follicular and DSL/MALT histology (P = .02; Fig 1A
When the TTF analysis was limited to the 85 patients with follicular lymphoma, the actuarial likelihood of remaining free from treatment failure at 5 and 10 years is 80% (± 5%) and 72% (± 5%), respectively. There was no difference in TTF between FSC and FM histology (P = .7). Only a stage-modified IPI score 2 (P = .02; Fig 2A) and an elevated ß2M (P = .07; Fig 2B) were associated with adverse TTF (Table 2). Because there was evidence that both serum ß2M and stage-modified IPI scores were associated with risk of failure, we investigated the independence of these associations by considering the four subsets of patients defined by categories of ß2M and stage-modified IPI. Curves for TTF are plotted in Fig 2C for these patient subsets. A formal bivariate test was not performed because of the small numbers of patients in the subsets.
Overall Survival There have been 22 deaths, including 13 among patients who had not suffered treatment failure before their death. The causes of death were related to lymphoma in seven, second cancers in eight, cardiac causes in one, an accident in one, and unknown causes in five. The actuarial 5- and 10-year survival rate is 92% (± 3%) and 82% (± 4%), respectively. The median survival has not been reached. Patients who had no residual disease evident at the initiation of therapy had a similar survival to other patients (P = .5), with a 10-year actuarial survival rate of 78% (± 9%).
For the 85 patients with follicular histology, the 5- and 10-year actuarial survival rates were 91% (± 3%) and 80% (± 5%), respectively. Survival did not differ between patients with follicular and DSL/MALT histology (P = .23; Fig 1B
Patterns of Relapse and Subsequent Survival Three of the 23 relapses were observed among the six patients who did not receive radiation therapy, and two of these relapses were late (11.3 and 13.1 years). Information on site of disease recurrence was available for 12 relapsing patients who received radiation therapy, and this was solely outside the radiation field in 10, and involved sites both within and outside the radiation field in two.
Among the 23 patients who relapsed, nine have died, with a median follow-up of surviving patients of 4.6 years from the date of relapse (range, 0 to 12.7). The 5- and 10-year actuarial survival rates after relapse are 54% (± 11%) and 46% (± 12%), respectively (Fig 4
Late Effects, Including Subsequent Malignancies As previously described, two patients developed myelodysplasia/AML; one patient had diploid cytogenetics, and karyotyping was not successful in the other. In addition to these two cases, there have been 12 other new malignancies observed, including four arising within radiation fields (one each of colonic, gastric, prostatic, and endometrial carcinomas). The other malignancies were four cases of lung cancer, and one case each of unknown primary site, Kaposi’s sarcoma, and ovarian and bladder cancers. Patients who developed a subsequent malignancy were slightly older at study entry (median, 58 v 55 years) than those who have not developed a subsequent malignancy Other late effects attributable to therapy were notably rare. As stipulated in the protocol, no patients received more than 450 mg/m2 of doxorubicin.28 Moreover, administration of doxorubicin by 48-hour continuous infusion was permitted; 61% of patients received doxorubicin by continuous infusion rather than bolus.
Despite changing concepts in the classification of malignant lymphomas, the pathologic recognition of follicular lymphoma has been consistently high and reproducible over many years,33 and such patients constituted more than 80% of those enrolled on the current study. The 10-year freedom from treatment failure rate of 72% and 10-year OS rate of 80% among patients with follicular lymphoma after combined-modality therapy in this prospective trial compare favorably with previously reported results in the literature.
There have been at least six studies reported analyzing more than 50 patients with clinically staged indolent, predominantly follicular, lymphomas treated with IF-XRT (Table 3
This study was drafted in 1983 using the International Working Formulation,30 before the clinicopathologic entities of extranodal marginal zone lymphoma of MALT and MCL were clearly recognized.35 During the period of our study accrual, they were generally considered to be within the category of low grade lymphoma, even MCL of the mantle zone type,36 explaining their eligibility for this study. Because MCL is now recognized to have a distinct natural history, the five patients with MCL were excluded from this analysis. For patients with DSL/MALT, the combined chemotherapy and IF-XRT approach reported here must be compared with the efficacy and relative simplicity of Helicobacter eradication therapy for patients with gastric MALT lymphoma.37 Nonetheless, it is notable that 100% of MALT lymphoma patients have remained free from relapse in our trial with follow-up to a maximum of 14 years. It is unclear whether long-term disease-free survival will be attained with antibiotic therapy. IF-XRT alone has achieved durable remissions in more than 90% of MALT lymphoma patients beyond 5 years,38,39 so any possible benefit from the addition of chemotherapy would be difficult to substantiate. However, because 25% to 34% of such patients will be shown to have disseminated disease after meticulous staging,40–42 late systemic relapses are possible in suboptimally staged patients treated with IF-XRT alone. The overall favorable results for the 102 patients in the current report have been achieved with good short-term tolerance,27,29 and a low incidence of treatment-related late adverse effects. Although not formally assessed in the current cohort of patients, the incidence of grade 3 or greater radiation-related late effects was 0% for patients with follicular lymphoma at our institution who were treated with 26.2 to 30.8 Gy radiation and 6% among those treated with 30.9 to 50.0 Gy.8 We observed two cases of myelodysplasia/AML during more than 1,000 patient years of follow-up in this cohort of older patients. Because it is possible that these were therapy-related events (alkylating agent, radiation, or both), they have been considered as treatment failures in all analyses. The incidence of secondary myelodysplasia/AML after alkylating agents and radiation therapy seems to plateau between 6 and 10 years after exposure.43–45 As the median follow-up of our trial is already at 10 years, further cases may not be encountered. Four patients developed solid tumors within radiation fields. Although these were tumor types common in the community, data from other cohorts indicate that the relative-risk of solid tumors among patients with lymphoma may be modestly increased to approximately 1.2-fold, with this risk greater in males.46,47 However, an increased risk of second tumors is also evident among chemotherapy-treated patients.46 Given the latency pattern of radiation-related tumors,48 it is possible that additional second cancers may develop with further follow-up. Current clinical practice,10 supported by dose-response data,6,8,11,12 to limit radiation doses to 25 to 35 Gy may minimize this risk.49
Concerns over the possibility of such late adverse effects, and the competing risk of death from unrelated causes in older patients, make selective application of combined modality treatment to those patients at high risk appealing.26 Some studies indicate that patients with stage II disease,6,8,9 bulky nodes,6,8,19 FM histology,9 or extranodal involvement9,19 are at a higher risk of relapse with IF-XRT alone, justifying the consideration of combined-modality therapy; however, these findings are not universal.7,34 Our favorable results are not due to a low proportion of patients with stage II disease, which is similar to prior studies (Table 3 There was a paradoxical association of superior survival with stage II disease and disease bulk. Given that these were not associated with similar trends in TTF, these apparent differences are likely a result of differences in the frequency of deaths from unrelated causes, or other factors such as the effect of therapy at relapse. The significant correlation of low serum ß2M with survival is more compelling, because the TTF impact of ß2M was consistent with the survival data. The prognostic importance of ß2M has been demonstrated in histologically aggressive lymphomas.50,51 Although an elevated serum ß2M was a highly significant adverse prognostic factor in univariate analysis in the original IPI study cohort, it was not considered in the IPI multivariate analysis due to incomplete data.52 A similar adverse prognostic effect of elevated serum ß2M has been reported in unselected groups of patients with low grade lymphomas,53,54 but this has not previously been examined specifically among patients with stage I–II disease. The cut point of 3 mg/dL has been utilized in these studies, but it does seem to behave as a continuous variable,53 consistent with the adverse outlook observed in our study with levels between 2.0 and 3.0 mg/dL. Similarly, although the IPI score was developed for histologically aggressive lymphomas,52 it is applicable to patients with advanced-stage, low grade disease.2,3 In the setting of stage I–II aggressive lymphoma, Miller et al32 developed the "stage-modified" IPI score. This has not previously been applied to patients with low grade lymphoma, but was able to usefully stratify patients in the current study, particularly for TTF. Because the observed survival after relapse in our study was quite good, as has previously been reported,19,55 the reduced stratification for survival is not surprising. One promising means of better identifying those patients with truly localized disease is functional imaging with [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Preliminary data demonstrate that, unlike older functional imaging modalities such as gallium or thallium scanning,56 more than 95% of cases of follicular lymphoma are FDG avid.57,58 Initial experience is that 42% of conventionally staged patients with apparently localized disease have been "up-staged" by PET.58 However, until such results are verified in larger series and FDG-PET scanning is more widely available, this procedure will not find widespread application. Although the current results seem to be better than previously reported with IF-XRT alone, they are based on nonrandomized comparisons across institutions. Based on this promising data, in 2000 the Trans-Tasman Radiation Oncology Group and the Australasian Leukemia and Lymphoma Group initiated a collaborative randomized study of IF-XRT versus IF-XRT followed by six cycles of COP using the schedule described in this article. Other chemotherapy options might merit investigation in conjunction with IF-XRT as well, including fludarabine-based regimens with or without monoclonal antibodies,59 which have proven effective in attaining molecular remissions with eradication of bcl-2 rearranged cells from the blood and marrow in the setting of advanced stage disease.60
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 versus > 2, (P = .3); IPI 2–3, ß2M 
